6-Phenethyl-3-piperidinecarboxamides

ABSTRACT

WHEREIN B is lower-alkylamino or morpholino, R1 is lower alkyl, and R2, R3 and R4 are hydrogen or lower alkoxy, have good antidepressant activity. Compounds of the formula

finite States Patent mi Sam [ Jan. 28, 1975 6-PHENETHYL-3-PIPERIDINECARBOXAMTDES [75] lnventor: Joseph Sam, Oxford, Miss.

[73] Assignee: The University of Mississippi,

University. Miss.

[22] Filed: Feb. 23, 1972 [2l] Appl. No: 228,768

[52] U.S. Cl 260/247.5 G, 260/293.76, 424/248 [51] Int. Cl C07d 87/40[58] Field of Search... 260/293.77, 247.5 R, 29376,

[56] References Cited UNITED STATES PATENTS 3,586,678 6/l97l Kuhnis ctul 260/293.76

Primary li.\'unziIwr-Donald (j. Dluus Ass/slam 1Llrum1'm'r.loso TovurAttorney, Agent, or Firm-Willium D. Stokes [57] ABSTRACT Compounds olthe formula 9 R AFB R3 Cl-l CI-i f wherein B is lower-alkylamino ormorpholino, R is lower alkyl, and R R and R are hydrogen or loweralkoxy, have good antidepressant activity.

7 Claims, N0 Drawings wherein B is lower-alkylamino or morpholino. R, islower alkyl, and R R and R are hydrogen or lower alkoxy,

The term lower alkyl as used herein per se and as 20 included in theterms lower alkoxy and loweralkylamino means saturated monovalentaliphatic radicals of the general formula C,,,H wherein m designates aninteger of less than six and is inclusive of both straight-chain andbranched-chain radicals. The

term lower-alkylamino as used herein means amino radicals of the generalformula NR R wherein R and R are the same or different and at least oneof which is lower alkyl.

The compounds of this invention may be conve niently synthesized byreactions involving first the conversion of6-methyl-3-pyridinecarboxylic acid with the appropriate amine to thecorresponding 6-methyl-3- pyridinecarboxamide (a), which can then bealkylated in the l-position to form a quaternary salt; i.e., a l-alkylpyridinium compound, with an alkyl halide; e.g., methyl, ethyl, propyliodides or bromides, etc., (b). The quaternary salt can next be reactedwith the appropriate benzaldehyde to form the corresponding stilbazolequaternary salt; i.e., a 6-styryl-l-alkyl pyridinium compound (c), whichcan then be converted by catalytic reduction; e.g., by hydrogenerationin the presence of a platinum oxide catalyst, to form thelalkyl-6-arylethyl-3-piperidinecarboxamide (d).

The above syntheses can be illustrated by the following equations:

ll ll @coou (C H N -0-c-oc a i C H OC-Cl 3 0 Ii 2 5 n 3 0 CH3 N N 0 ll/\/C B 3" (b) O O u H -C-B i CH 4 i E-k 3 O H R 6-15 2 C E R O 3.\N+/ al X C-B l Hem-l R3 X EXAMPLE 1l-methyl-6-phenethy1-3-diethylaminocarbonylpiperidine il C- N (C 11 2 0Cll Cll t N a. To a stirred and cooled mixture of 6-methyl-3- CH:CH Red.j 9 0 I pyridinecarboxylic acid (0.1 mole, 13.7 g.) and 250 ml.

methylene chloride, triethylamine (0.1 mole, 10.1 g.) was addedgradually. The resulting clear solution was kept at 0-3C., while ethylchloroformate (0.1 1 mole, 10.5 ml.) was added dropwise with stirringover about 15 minutes. While maintaining the temperature at 0-3C.throughout, the mixture was stirred for minutes and then diethylamine(0.1 mole, 7.3 g.) was added dropwise. After warming to roomtemperature, the mixture was washed with 300 ml. water and the methylenechloride phase was separated, dried over anhydrous potassium carbonateand distilled to give 6- methyl-3-diethylaminocarbonylpyridine.

b. A solution of 6-methyl-3-diethylaminocarbonyl-- pyridine (0.05 mole,9.8 g.) and methyl iodide (0.06 mole, 8.5 g.) in 300 ml. benzene washeated to reflux for 20 hours. The solid quaternary salt, 6-methyl-3-diethylaminocarbonyl-l-methylpyridinium iodide, which formed as aprecipitate, was filtered off and recrystallized from ethanol.

c. A solution of 6-methyl-3-diethylaminocarbonyl-1- methylpyridiniumiodide (0.02 mole, 6.8 g.), benzaldehyde (0.04 mole, 4.2 g.) andpiperidine (1.0 ml.) in ml. dimethyl formamide was stirred at roomtemperature for 24 hours. After evaporation of the solvent under reducedpressure, the residue was treated with 100 ml. cold water. Theprecipitate was removed by filtration, washed thoroughly with coldwater, then with ether and recrystallized from acetonitrile, to give 5.6g. of the stilbazole quaternary salt, 6-styryl-3-diethylaminoearbonyl-l'methylpyridinium iodide, M.P. 204-205 C.

Analysis. Calculated for C H lN Oz C, 54.01; H, 5.49; N, 6.64. Found: C,53.84; H, 5.65; N, 6.94.

d. A suspension of this stilbazole quaternary salt (0.01 mole, 4.3 g.)in 60 ml. water was hydrogenated in the presence of 0.5 g. platinumoxide catalyst at 48 psi for 24 hours. After removal of the catalyst byfiltration, the filtrate was neutralized with saturated sodium carbonatesolution and then extracted three times with 50 ml. methylene chloride.After drying over anhydrous magnesium sulphate and evaporation of thesolvent, the product was purified by elution chromatography usingneutral alumina land anhydrous ether as the eluent, to give 2.3 g.l-methyl-6-phenethyl-3-diethylaminocarbonylpiperidine, B.P. 166170C./0.35 mm., m, 1.5190.

Analysis. Calculated for C H N O: C, 75.45; H, 10.00; N, 9.26. Found: C,75.07; H, 10.36; N, 9.28.

EXAMPLE 2 l-methyl-6-( 3 ,4-dimethoxyphenethyl)-3-diethylaminocarbonylpiperidine oca i C11 0 CH CH N 1 The proceduresset forth in Example 1 were repeated, except that in step (c), thebenzaldehyde was replaced by 3,4-dimethoxybenzaldehyle (0.04 mole, 6.6g.), to give 4.1 g. of the stilbazole quaternary salt,6-(3,4-dimethoxystyryl)-3-diethylaminocarbonyl-1- methyI-pyridiniumiodide, M.P. 18()-l81C.

Analysis. Calculated for C ,H ,lN 0,,; C, 52.28; H, 5.64; N, 5.81.Found: C, 51.94; H, 5.97; N, 5.91.

In step (d), the reduction of this stilbazole quaternary salt (0.008mole, 3.9 g.) gave 2.2 g. l-methyl-6-(3,4dimethoxyphenethyl)-3-diethylaminocarbonylpiperidine, n 1.5224.

Analysis. Calculated for C H N O C, 69.58; H, 9.45; N, 7.73. Found: C,69.83; H, 9.98; N, 7.74.

EXAMPLE 3 l-methyl-6-( 3,4.5-trimethoxyphenethyl)-3-diethylaminocarbonylpiperidine e3 0 CH2CH2 L N EXAMPLE 4l-methyl-6-phenethyl-3-( 4-morpholinocarbonyl piperidine meat 0 ca ca Ua. To a stirred and cooled mixture of 6-methyl-3- pyridinecarboxylicacid (0.1 mole, 13.7 g.) and 250 ml. methylene chloride, triethylamine(0.1 mole, 10.1 g.) was added gradually. The resulting clear solutionwas kept at 0-3 C. while ethyl chloroformate (0.1 1 mole, 10.5 ml.) wasadded dropwise with'stirring over about minutes. While maintaining thetemperature at 0-3 C. throughout, the mixture was stirred for 30 minutesand then morpholine (0.1 mole, 8.7 g.) was added dropwise. After warmingto room temperature, the mixture was washed with 300 ml. water and themethylene chloride phase was separated, dried over anhydrous potassiumcarbonate and distilled to give 6-methyl-3-(4-morpholinocarbonyl)pyridine.

b. A solution of 6-methyl-3-(4-morpholinocarbonyl)- pyridine (0.0, mole,10.5 g.) and methyl iodide (0.06 mole. 8.5 g.) in 300 ml. benzene washeated to reflux for hours. The solid quaternary salt 6-methyl-3-(4-morpholinocarbonyl 1 -methylpyridinium iodide, which formed as aprecipitate, was filtered off and recrystallized from ethanol.

c. A solution of 6-methyI-3-(4-morpholinocarbonyl)- l-methylpyridiniumiodide (0.02 mole, 7.1 g.), benzaldehyde (0.04 mole, 4.2 g.) andpiperidine (1.0 ml.) in 35 ml. dimethyl formamide was stirred at roomtemperature for 24 hours. After evaporation of the solvent under reducedpressure, the residue was treated with 100 ml. cold water. Theprecipitate was removed by filtration, washed thoroughly with coldwater, then with ether and recrystallized from acetonitrile. to give 5.4g. of the stilbazole quaternary salt, 6-styryl-3-(4-morpholinocarbonyl)-l-methylpyridinium iodide, M.P. 206-208 C.

Analysis. Calculated for C IH IN O C, 52.06; H, 4.83; N, 6.39. Found: C,52.29; H, 4.85; N, 6.21.

d. A suspension of this stilbazole quaternary salt (0.01 mole, 4.4 g.)in 60 ml. water was hydrogenated in the presence of 0.5 g. platinumoxide catalyst at 48 psi for 24 hours. After removal of the catalyst byfiltration, the filtrate was neutralized with saturated sodium carbonatesolution and then extracted three times with 50 ml. methylene chloride.After drying over anhydrous magnesium sulphate and evaporation of thesolvent, the product was purified by elution chromatography usingneutral alumina l and anhydrous ether as the eluent, and thenrecrystallized from ether-n-hexane, to give 2.6 g.l-methyl-6-phenethyl1-3-(4-morpholinocarbonyl)piperidine, M.P. l02-l03C., n 1.5399.

Analysis. Calculated for G i-1 N 0 C, 72.12; H, 8.92; N, 8.85. Found: C,72.51; H, 9.19; N, 8.56.

EXAMPLE 51-methyl-6-(3,4-dimethoxyphenethyl)-3-(4-morpholinocarbonyl)piperidineC11 0 CH CH l EXAMPLE 61-methy1-6-(3,4,5-trimethoxyphenethyl)-3-(4-morpholinocarbonyl)piperidineoca 3 ,9 /[c -1.- 0 0 CHZCHFL 1 u The procedures set forth in Example 4were repeated, except that in step (c), the benzaldehyde was replaced by3,4,5-trimethoxybenzaldehyde (0.04 mole, 7.8 g.). to give 6.0 g. of thestilbazole quaternary salt.6-(3.4.5-trimethoxystyryl)-3-(4-morpholinocarbonyl)- l'methylpyridiniumiodide, M.P. 230-232 C.

Analysis. Calculated for C H ,lN O,,: C. 50.19; H, 5.17; N, 5.32. Found:C, 50.51; H, 5.73; N. 5.12.

In step (d the reduction of this stilbazole quaternary salt (0.01 mole,5.3 g.) gave 3.3 g. l-methyl-6-(3.4,5- trimethoxyphenethyl )-34-morpholinocarbonyl piperidine, m, 1.5405.

ANTIDEPRESSANT ACTIVITY IN MICE All of the I-alkyl-6-aryIethyl-3-pipcridinccarboxamide compounds prepared in accordance with the aboveexamples were shown to possess moderate to marked antidepressantactivity in DOPA response potentiation tests in mice. The table belowshows the increase in motor activity due to the potentiation effect atthe indicated dosage of each of thelaIkyl-6-arylethyl-3-piperidinecarboxamide compounds of Examples 1 to 6,as well as a comparison with amitryptyline, a compound known to haveantidepressant activity.

What is claimed is: l. A pipcridinc of the formula wherein B is a memberselected from the group consisting of lower-alkylamino and morpholino,R, is lower alkyl, and R R and R are each a member selected from thegroup consisting of hydrogen and lower alkoxy.

2. A compound according to claim 1 which islmethyl-6-phenethyl-3-diethylaminocarbonylpiperidine.

3. A compound according to claim 1 which islmethyl-6-(3,4-dimethoxyphenethyl)-3-diethylaminocarbonylpiperidine.

4. A compound according to claim 1 which ismethyl-6-(3,4,5-trimethoxyphenethyl)-3-diethylaminocarbonylpiperidine.

5. A compound according to claim 1 which is I-methyI-6-phenethyI-3(4-morpholinocarbonyl)piperidine.

6. A compound according to claim 1 which islmethyl-6-(3,4-dimethoxyphenethyl)-3-(4-morpholinocarbonyl)piperidine.

7. A compound according to claim 1 which is I- methyl-6-(3,4,5-trimethoxyphenethyl )-3-(4-morpholinocarbonyl)piperidine.

I i i t t

2. A compound according to claim 1 which is1-methyl-6-phenethyl-3-diethylaminocarbonylpiperidine.
 3. A compoundaccording to claim 1 which is1-methyl-6-(3,4-dimethoxyphenethyl)-3-diethylaminocarbonylpiperidine. 4.A compound according to claim 1 which is1-methyl-6-(3,4,5-trimethoxyphenethyl)-3-diethylaminocarbonylpiperidine.5. A compound according to claim 1 which is1-methyl-6-phenethyl-3(4-morpholinocarbonyl)piperIdine.
 6. A compoundaccording to claim 1 which is1-methyl-6-(3,4-dimethoxyphenethyl)-3-(4-morpholinocarbonyl)piperidine.7. A compound according to claim 1 which is1-methyl-6-(3,4,5-trimethoxyphenethyl)-3-(4-morpholinocarbonyl)piperidine.